Project Summary I, Andrew Hudson, am an anesthesiologist with a Ph.D in neurophysiology who is seeking to become a fully independent, funded physician-scientist investigating the systems neuroscience of anesthesia and recovery of consciousness. The immediate goals of this proposal are to solidify my core knowledge in neuroscience and update my laboratory and analytic techniques while building my publication record and establishing preliminary data for an R01 application. My proposed research program seeks to understand the impact of anesthetics on a population level in the intact nervous system, with the longer term goal of understanding how these shifts in neuronal circuit properties lead to recovery of consciousness from anesthesia. My mentor, Dr. Joshua Trachtenberg in the Department of Neurobiology at UCLA, will be responsible for my scientific development, teaching me the optical and genetic techniques that have been developed since completion of my time in graduate school. My co-mentor, Dr. Aman Mahajan in the Department of Anesthesiology and Perioperative Medicine will help me navigate the many pitfalls associated with establishing independence as a physician scientist. In this effort I will be greatly aided by a committee of advisors, including Drs Dan Cole and Barbara Van De Weile from the Department of Anesthesiology and Perioperative Medicine at UCLA, who will help ensure I am developing as a professional in the operating room, within my institution, and within my professional organizations. Dr. Hugh Hemmings, an expert in molecular mechanisms of anesthesia at Weill Medical College of Cornell University will meet with me twice a year to review my work and help me refine my presentation and analytic skills. Dr. Donald Pfaff, an expert in arousal and attention systems in the brain, will also meet with me twice a year to review my work and offer insights about subcortical contributions to this cortico-centric project. Beyond my active participation in cutting-edge research, I will supplement my knowledge base through carefully selected coursework here at UCLA, focusing on the acquisition and analysis of large image based datasets, modeling of circuit changes in the nervous system, and the ethical conduct of research. My project proposal seeks to dissect the effects of anesthetics on individual members of the cortical microcircuit, with special interest in inhibitory interneurons. I consider three subtypes of inhibitory interneurons for investigation, based upon their expression of either parvalbumin (PV), somatostatin (SOM), or vasoactive intestinal peptide (VIP). Each of these populations is likely to contribute a different specific function of the cortical microcircuit, and because each population has a unique expression profile, they are likely to be differentially susceptible to anesthetics. I hypothesize that differential susceptibility of these different inhibitory populations contributes to the changes in spontaneous electrical activity observed at different anesthetic depths. By then selectively targeting and intervening in these populations using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) I hope to go beyond a correlative account of what happens in anesthetized brain circuits to a causal investigation of the changes in the brain that lead to unconsciousness from anesthesia and the resulting recovery of consciousness after anesthesia.